The present invention relates to a process for preparing N.sup.6,9-disubstituted adenines, and more particularly to a process for preparing N.sup.6,9disubstituted adenines in high yields and good selectivity by the alkylation of metal salts of N.sup.6 -substituted adenines with substituted benzyl halide.
Known processes for preparing N.sup.6,9-disubstituted adenines are hard to adopt to the industrial production, because of complication of process steps or use of expensive raw materials. Among them, a process as disclosed in U.S. Pat. No. 4,189,485 attracts attention, because of its simple process. However, the yield of the product is low and is at most 60 %. Moreover, since the undesired 3-isomer is by-produced, it is expected that the yield of the desired 9-isomer is very low.
The N.sup.6,9-disubstituted adenines are compounds useful as plant growth regulators, antivirotics and anticoccidial agents, and in recent years, the use as anticoccidial agents has been particularly watched. In case that they are used as anticoccidial agents, it is necessary to control the incorporation of the 3-isomer by-produced generally upon alkylating adenine derivatives in alkaline mediums in as trace amounts as possible, i.e. below 100 p.p.m.
U.S. Pat. No. 4,171,440 discloses a process for the purification of 9-(2,6-dihalobenzyl)adenines which are similar compounds to the N.sup.6,9-disubstituted adenines. In this process, the undesired 3-isomer is removed by treating the 9-isomer containing the 3-isomer with concentrated sulfuric acid by utilizing the property of the 3-isomer based on the thermodynamic instability. This purification process has the disadvantages that the procedure is very complicated and the use of large quantities of concentrated sulfuric acid is necessary.
It is known that N.sup.6 -substituted adenines used as intermediates in the process of the present invention are prepared by reacting 6-hydroxypurine with phosphorus oxychloride and reacting the resulting 6-chloropurine with a corresponding amine, as disclosed in Japanese Examined Patent Publication (Tokkyo Kokoku) No. 3319/1968, No. 6222/1968 and No. 27649/1969 and J. Am. Chem. Soc., Vol. 79, 2251(1957). These processes have the disadvantage of being unsuitable for industrialization, since the reactions are carried out in two steps and raw materials are expensive. For instance, in the preparation of 6-chloropurine from 6-hydroxypurine, expensive phosphorus oxychloride is used as a chlorinating agent, and also the yield thereof is not so high, i.e. 50 to 60 %. Further, the post-treatment of the reaction and the recovery of the product are difficult. Since anticoccidial agents are very inexpensive as compared with pharmaceuticals, it is required that intermediates used for the preparation of anticoccidial agents are very inexpensive.
It is an object of the present invention to provide a process for preparing N.sup.6,9-disubstituted adenines in high yields and high purities.
A further object of the invention is to provide a process for preparing N.sup.6,9-disubstituted adenines in high yields and high purities by the reaction of N.sup.6 -substituted adenines with benzyl halide compounds.
Another object of the invention is to provide a process for preparing N.sup.6,9-disubstituted adenines from adenine through N.sup.6 -substituted adenines.
A still another object of the invention is to provide a process for preparing pure N.sup.6,9-disubstituted adenines having a low content of impurities, N.sup.6,3-disubstituted adenines.